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1232 www.thelancet.com Vol 382 October 12, 2013

In The Lancet, Sophie Jamal and colleagues1 report an updated systematic review and meta-analysis of the eff ect on mortality of treatment of chronic kidney disease hyperphosphataemia with calcium-based versus non-calcium-based phosphate binders. Kidneys excrete excess dietary phosphate, therefore loss of renal function leads to a positive phosphate balance that ultimately results in hyperphosphataemia. Excess phosphate might deposit in soft tissues, most notably the cardiovascular system, as calcium phosphate salts. Observational studies have linked high serum phosphate concentrations with adverse outcomes in patients with chronic kidney disease and, more recently, the general population.2 The phosphate removal capacity of dialysis is limited. Thus, chronic kidney disease clinical practice guidelines suggest dietary restriction of phosphate and use of phosphate binders to treat hyperphosphataemia.3

In the late 1980s, calcium-based phosphate binders were the treatment of choice for hyperphosphataemia associated with chronic kidney disease. Calcium-based binders had allowed aluminium-based binders

to be phased out, a full decade after aluminium was linked to dialysis encephalopathy.4 A mean dose of 8·5 g (range 2·5–17) per day of calcium carbonate had been reported to control hyperphosphataemia in patients on dialysis,5 which implied a mean of 3·4 g per day supplemental elemental calcium (up to a maximum of 6·8 g per day), well above the 2011 Institute of Medicine tolerable upper intake of 2·0 g per day for adults older than 50 years. To put this in perspective, the recommended daily calcium dietary allowance is 0·8–1·2 g for adults, and the tolerable upper intake of calcium was lowered in 2011. Emerging evidence suggests that calcium supplementation can have potential adverse cardiovascular eff ects in the general population.6

Kidney failure also impairs the capacity to excrete excess calcium. Calcium from binders is absorbed, as shown by increased urinary calcium excretion.7 The problem might be compounded by absorption of alkali present in calcium-based binders and by concomitant use of vitamin D for secondary hyperparathyroidism. The concomitant supply of alkali and calcium is the basis

The demise of calcium-based phosphate binders

CMGC is on advisory boards for Bayer, Novartis, and Roche; and has received honoraria for travel and service on advisory boards, and research support from these companies. TYW is on advisory boards for Abbott, Allergan, Bayer, Novartis, Roche, and Pfi zer; has received honoraria for travel and service on advisory boards, and research support from these companies; and has provided expert testimony to Novartis.

1 Lim LS, Mitchell P, Seddon JM, Holz FG, Wong TY. Age-related macular degeneration. Lancet 2012; 379: 1728–38.

2 Wong TY, Liew G, Mitchell P. Clinical update: new treatments for age-related macular degeneration. Lancet 2007; 370: 204–06.

3 Rosenfeld PJ, Brown DM, Heier JS, et al. Ranibizumab for neovascular age-related macular degeneration. N Engl J Med 2006; 355: 1419–31.

4 Brown DM, Kaiser PK, Michels M, et al. Ranibizumab versus verteporfi n for neovascular age-related macular degeneration. N Engl J Med 2006; 355: 1432–44.

5 Cheung N, Wong TY. Changing trends of blindness: the initial harvest from translational public health and clinical research in ophthalmology. Am J Ophthalmol 2012; 153: 193–95.

6 Levinson DR. Review of Medicare part B Avastin and Lucentis treatments for age-related macular degeneration. Sept 6, 2011. Washington, DC: Department of Health and Human Services, 2011. http://oig.hhs.gov/oas/reports/region10/11000514.pdf (accessed July 10, 2013).

7 Curtis LH, Hammill BG, Shulman KA, Cousins SW. Risks of mortality, myocardial infarction, bleeding and stroke associated with therapies for age-related macular degeneration. Arch Ophthalmol 2010; 128: 1273–79.

8 Lim LS, Cheung CMG, Mitchell P, Wong TY. Emerging evidence concerning systemic safety of anti-VEGF agents—should ophthalmologists be concerned? Am J Ophthalmol 2011; 152: 329–31.

9 Chakravarthy U, Harding SP, Rogers CA, et al, on behalf of the IVAN study investigators. Alternative treatments to inhibit VEGF in age-related choroidal neovascularisation: 2-year fi ndings of the IVAN randomised controlled trial. Lancet 2013; published online July 19. http://dx.doi.org/10.1016/S0140-6736(13)61501-9.

10 The CATT Research Group. Ranibizumab and bevacizumab for neovascular age-related macular degeneration. N Engl J Med 2011; 364: 1897–1908.

11 The CATT Research Group. Ranibizumab and bevacizumab for neovascular age-related macular degeneration: two-year results. Ophthalmology 2012; 119: 1388–98.

12 IVAN Study Investigators, Chakravarthy U, Harding SP, et al. Ranibizumab versus bevacizumab to treat neovascular age-related macular degeneration: one-year fi ndings from the IVAN randomized trial. Ophthalmology 2012; 119: 1399–411.

13 Finger RP, Wiedemann P, Blumhage F, Pohl K, Holz FG. Treatment patterns, visual acuity and quality-of-life outcomes of the WAVE study— a noninterventional study of ranibizumab treatment for neovascular age-related macular degeneration in Germany. Acta Ophthalmol 2012; published online Nov 22. DOI:10.1111/j.1755-3768.2012.02493.x.

14 Cohen SY, Dubois L, Tadayoni R. Results of one-year’s treatment with ranibizumab for exudative age-related macular degeneration in a clinical setting. Am J Ophthalmol 2009; 148: 409–13.

15 Chakravarthy U, Wong TY, Fletcher A, et al. Clinical risk factors for age-related macular degeneration: a systematic review and meta-analysis. BMC Ophthalmol 2010; 10: 31.

16 Wong TY, Klein R, Sun C, et al, for the Atherosclerosis Risk in Communities Study. Age-related macular degeneration and risk for stroke. Ann Intern Med 2006; 145: 98–106.

17 Heier JS, Brown DM, Chong V, et al. Intravitreal afl ibercept (VEGF trap-eye) in wet age-related macular degeneration. Ophthalmology 2012; 119: 2537–48.

18 Boyer DS. A Phase 2b study of Fovista, a platelet derived growth factor (PDGF) inhibitor in combination with a vascular endothelial growth factor (VEGF) inhibitor for neovascular age-related macular degeneration (AMD). Association for Research in Vision and Ophthalmology Annual Meeting; Seattle, WA, USA; May 5–9, 2013. 2175.

Published OnlineJuly 19, 2013

http://dx.doi.org/10.1016/S0140-6736(13)61165-4

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of the milk-alkali syndrome of soft tissue calcifi cation. We have witnessed severe cardiovascular calcifi cation in patients on long-term calcium-based binders and vitamin D. Concerns about the potential dangers of excess calcium led to development of non-calcium phosphate binders such as sevelamer in 1997 and, later, lanthanum.8 However, despite the pathophysiological logic suggesting that combined calcium and phosphate accumulation is not desirable in patients with chronic kidney disease, until recently no proof existed to show that use of non-calcium-based binders improved out comes. Absence of evidence of improved outcomes and the four to 70 times lower yearly cost of calcium-based binders than of non-calcium-based binders were cited as reasons to consider calcium-based agents as fi rst-line phosphate binders for patients undergoing dialysis in a 2010 review9—unchanged from 25 years ago. Recent international guidelines recommend restricting the dose of calcium-based phosphate binders only when hypercalcaemia is persistent or recurrent, and suggest restricting the dose in patients with arterial calcifi cation or persistently low concentrations of serum parathyroid hormone.3 The suggestion was in line with concerns that iatrogenic calcifi cation might occur in patients with high vascular calcifi cation prevalence.

Jamal and colleagues1 have now addressed the un-solved clinical problem of what the optimal therapy for kidney-disease-associated hyperphosphataemia is.1 In 11 randomised controlled trials, 2312 patients randomly assigned to non-calcium-based phosphate binders had a 22% reduction in all-cause mortality compared with 2310 patients assigned to calcium-based binders (risk ratio 0·78, 95% CI 0·61–0·98). Analysed trials were limited by small sample size and short follow-up: only one randomised controlled trial with 212 patients had a follow-up longer than 24 months. A survival diff erence was reported despite the fact that short duration of most trials might have biased against observing a diff erence, since a lag period is thought to be needed for calcifi cation to progress.

How does this compare with trials targeting traditional cardiovascular risk factors in chronic kidney disease? The Study of Heart and Renal Protection (SHARP)10 was the fi rst trial to show a benefi t of lipid-lowering therapy in chronic kidney disease: a 17% reduction in major atherosclerotic events. Despite following up 9270 patients for a median of 4·9 years, SHARP did not fi nd evidence of survival diff erences. Thus, Jamal and colleagues’ fi nding

that choice of phosphate binder might lower mortality is clinically signifi cant. In their meta-analysis of seven randomised trials (704 patients) that measured coronary artery calcifi cation, non-calcium-based phosphate binders resulted in less progression of vascular calcifi cation at the longest follow-up for each study.1 This result suggests that cardiovascular calcifi cation has a potential role in the diff erent outcomes.

The study did not address whether phosphate binders decrease mortality when compared with no treat ment, whether non-calcium-based phosphate binders are inherently benefi cial or whether calcium-based binders are harmful, whether the fi ndings apply to other non-calcium-based binders (such as soon-to-be commercialised iron-based binders),11 or whether diff erences exist between sevelamer and lanthanum or between diff erent calcium-containing binders. No study assessing binders containing both calcium and magnesium—which might have diff erent adverse eff ects from calcium-based binders—was included in this meta-analysis.

The study could have wider repercussions as evidence accumulates that excess phosphate might be harmful in people other than those with chronic kidney disease.2 In this respect, defi ciency of the phosphaturic hormone Klotho is associated with phosphate-related accelerated ageing and premature mortality in mice.12 Chronic kidney disease represents a klotho defi ciency state.13 Further more, systemic infl ammation, a predictor of clinical outcomes, decreases kidney klotho.14

Is Jamal and colleagues’ study a game changer in the choice of phosphate binders? High-quality meta-analyses and systematic reviews of randomised con-trolled trials can be used as evidence to support a recommendation. Physicians’ perception of the cost-eff ectiveness of phosphate-binder choices might change following this meta-analysis and the expected cost reduction after patents for non-calcium-based phosphate binders start expiring in 2014.

*Alberto Ortiz, Maria Dolores Sanchez-NiñoNephrology and Hypertension Department, Instituto de Investigación Sanitaria de la Fundación Jiménez Díaz and Universidad Autónoma de Madrid, Instituto Reina Sofía de Investigación Nefrológica (AO) and Nephrology Department, Instituto de Investigación Hospital Universitario La Paz (MDS-N), La Red de Investigación Renal, 28040 Madrid, Spainaortiz@fj d.es

Comment

1234 www.thelancet.com Vol 382 October 12, 2013

In April, 2013, new guidance for phase 3 clinical trials in patients with schizophrenia came into eff ect.1 The guidance, issued by the European Medicines Agency (EMA),2 is intended to guide the design of regulatory studies of new antipsychotic drugs requiring a market-ing authorisation for schizophrenia in Europe. Here, we report some aspects of this offi cial document that could negatively aff ect assessment of drugs for schizophrenia, together with some possible solu-tions. Schizophrenia is a particularly challenging area, because several active treatments are already available, placebo response is high, and treatment response can be erratic and variable.3

The fi rst issue is that the EMA does not require drug companies to provide information about all clinical studies that have concluded when they submit a drug for approval, meaning that they can select what data to present. Therefore, regulators have to base the crucial decision about whether a new drug should obtain a marketing authorisation on only a sample of studies, without consideration of all available evidence.

The EMA does not stipulate that studies submitted for regulation are registered in an international reposi-tory of study protocols. This issue is related to the fi rst, because regulators cannot know how many trials have been done and how many of these have been included

in the submission package if the trials have not been registered.

Additionally, the EMA recommends that studies of the acute treatment of schizophrenia have three groups, comparing the new product with both placebo and an active comparator. Superiority to placebo is explicitly required, but non-inferiority to an active comparator is not mentioned as a compulsory requirement. This policy may not be relevant when no standard treatments are available, but might be problematic when eff ective agents are available, such as those for schizophrenia.4 It could allow approval of drugs that might have a less favourable profi le than those already on the market. Additionally, stipulation of placebo groups for comparison could systematically exclude patients with severe symptoms of schizophrenia, because physicians might be reluctant to enrol severely ill patients into a random procedure that could result in placebo treatment for several weeks. The EMA does accept two-arm studies comparing a new drug with an active comparator as an alternative, provided superiority is shown.

According to regulatory scientists, a placebo group should not be used when eff ective agents are available; instead, demonstration of superiority to an active com-parator should be compulsory.5 This position, how ever,

Regulatory science in Europe: the case of schizophrenia trials

AO has received consultancy fees, honoraria, and speakers’ fees from Sanofi , Genzyme, Fresenius Medical Care, and Amgen; research funding or funding for equipment or drugs from Fresenius Medical Care; and travel or accommodation payments from Genzyme, Fresenius Medical Care, Shire, Amgen, Baxter, Rubió, and Abbott. MDS-N has received consultancy fees, honoraria, and speakers’ fees from Genzyme.

1 Jamal SA, Vandermeer B, Raggi P, et al. Eff ect of calcium-based versus non-calcium-based phosphate binders on mortality in patients with chronic kidney disease: an updated systematic review and meta-analysis. Lancet 2013; published online July 19. http://dx.doi.org/10.1016/S0140-6736(13)60897-1.

2 Gonzalez-Parra E, Tuñón J, Egido J, Ortiz A. Phosphate: a stealthier killer than previously thought? Cardiovasc Pathol 2012; 21: 372–81.

3 Kidney Disease: Improving Global Outcomes (KDIGO) CKD-MBD Work Group. KDIGO clinical practice guideline for the diagnosis, evaluation, prevention, and treatment of chronic kidney disease-mineral and bone disorder (CKD-MBD). Kidney Int Suppl 2009; 113: S1–13.

4 Alfrey AC, LeGendre GR, Kaehny WD. The dialysis encephalopathy syndrome. Possible aluminum intoxication. N Engl J Med 1976; 294: 184–88.

5 Slatopolsky E, Weerts C, Lopez-Hilker S, et al. Calcium carbonate as a phosphate binder in patients with chronic renal failure undergoing dialysis. N Engl J Med 1986; 315: 157–61.

6 Bolland MJ, Grey A, Avenell A, Gamble GD, Reid IR. Calcium supplements with or without vitamin D and risk of cardiovascular events: reanalysis of the Women’s Health Initiative limited access dataset and meta-analysis. BMJ 2011; 342: d2040.

7 Block GA, Wheeler DC, Persky MS, et al. Eff ects of phosphate binders in moderate CKD. J Am Soc Nephrol 2012; 23: 1407–15.

8 Chertow GM, Burke SK, Lazarus JM, et al. Poly[allylamine hydrochloride] (RenaGel): a noncalcemic phosphate binder for the treatment of hyperphosphatemia in chronic renal failure. Am J Kidney Dis 1997; 29: 66–71.

9 Tonelli M, Pannu N, Manns B. Oral phosphate binders in patients with kidney failure. N Engl J Med 2010; 362: 1312–24.

10 Baigent C, Landray MJ, Reith C, et al, for the SHARP Investigators. The eff ects of lowering LDL cholesterol with simvastatin plus ezetimibe in patients with chronic kidney disease (Study of Heart and Renal Protection): a randomised placebo-controlled trial. Lancet 2011; 377: 2181–92.

11 Wüthrich RP, Chonchol M, Covic A, Gaillard S, Chong E, Tumlin JA. Randomized clinical trial of the iron-based phosphate binder PA21 in hemodialysis patients. Clin J Am Soc Nephrol 2013; 8: 280–89.

12 Ohnishi M, Razzaque MS. Dietary and genetic evidence for phosphate toxicity accelerating mammalian aging. FASEB J 2010; 24: 3562–71.

13 Hu MC, Shi M, Zhang J, et al. Klotho defi ciency causes vascular calcifi cation in chronic kidney disease. J Am Soc Nephrol 2011; 22: 124–36.

14 Moreno JA, Izquierdo MC, Sanchez-Niño MD, et al. The infl ammatory cytokines TWEAK and TNFα reduce renal klotho expression through NFκB. J Am Soc Nephrol 2011; 22: 1315–25.

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Published OnlineJune 21, 2013

http://dx.doi.org/10.1016/S0140-6736(13)60255-X